UVR Induces DNA Methylation Changes in Melanocytes

Abstract

Cutaneous malignant melanoma is the deadliest form of skin cancer with a rising incidence rate. Epidemiological studies show exposure to ultraviolet radiation (UVR) cause 80% of melanomas. However, the underlying molecular mechanisms by which UVR promotes melanomagenesis are unclear. The mutagenic properties of UVR are incontrovertible; however, well-studied driver mutations of melanomagenesis (BRAF V600E and NRAS Q61L/R) do not bear UVR signature mutations and so the role UVR mutations play in the early initiation of melanoma remains controversial. This highlights the gap in knowledge of the initial critical molecular mechanisms of UVR-induced melanomas and warrant investigating non-mutational mechanisms as causal factors of UVR-induced melanomagenesis. Aberrant DNA methylation is a signature of melanoma and regulates expression of important tumor suppressors. While epigenetic dysregulation is an important aspect of melanoma etiology, it has never been investigated in the context of UVR. We hypothesize that these initial UVR-induced DNA methylation changes may sensitize a field of melanocytes to acquiring subsequent complementary spontaneous and/or UVR-induced genetic mutations and render them susceptible to melanomagenesis. My preliminary data demonstrate that UVR can modulate DNA methylation in melanocytes and suggests a pigment dependent mechanism. UVR-induced DNA methylation changes in highly pigmented melanocytes primarily in intergenic regions as areas of active transcription were protected from 5’mC changes. Additionally, UVR induced long-term transcriptional changes in both dark and light pigmented melanocytes suggesting multiple epigenetic mechanisms being altered. Evaluation of the protein regulation of the enzymes involved in writing or erasing 5’mC point towards a dysregulation in TET2. Further work is needed to determine if changes in TET2 could contribute to the observed methylation changes. To determine if these methylation changes had any significance to melanoma development, they were compared to the skin cutaneous melanoma cohort in the TCGA database which found a modest correlation in UVR-induced methylation changes and those found in melanoma patients. Interestingly, 5’mC at UVR-sensitive sites was prognostic of patient survival. A highly pigmented human melanoma cell line was UV-irradiated to see if DNA methylation can also be affected in transformed cells; however, no changes were observed. This suggests UV-induced methylation contributes to early changes in melanoma development and/or other relevant physiological changes within the melanocytes. Altogether, these data identify a novel non-mutation mechanism by which UVR may contribute of melanomagenesis.